Trans-hexahydrobenzophenanthridines of the formula ##STR1## wherein R is hydrogen or C1 -C4 alkyl; R1 is hydrogen, benzoyl or pivaloyl; and x is hydrogen, chloro, bromo, iodo or a group of the formula OR2, are novel ligands for dopamine receptors.
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1. A compound of the formula ##STR4## wherein Ha and Hb are trans across ring fusion bond c; R is hydrogen or C1 -C4 alkyl;
R1 is hydrogen, benzoyl or pivaloyl; X is hydrogen, chloro, bromo, iodo or a group of the formula --OR2 wherein R2 is hydrogen, benzoyl or pivaloyl, provided that when X is a group of the formula OR2, the groups R1 and R2 can be taken together to form a group of the formula --CH2 --.
3. The compound of
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This invention relates to novel ligands for dopamine receptors. More particularly this invention is directed to certain substituted trans-hexahydrobenzo[a]phenanthridine compounds useful as dopamine-like agents or as dopamine receptor blockers.
Drugs with a dopamine-like action, or an ability to block (antagonize) dopamine receptors are of therapeutic interest for a variety of reasons. First, it is known that certain dopamine-like substances may have utility as agents to control hypertension. Recently, two compounds SKF 38393 and SKF 82526 (Fenoldopam) have been clinically evaluated by Smith-Kline laboratories as novel antihypertensives. Both of those compounds are dopamine-like agents that act specifically at dopamine D-1 receptors. Presently none of the marketed antihypertensive agents work by this mechanism, but there is a great interest by the pharmaceutical industry in evaluating agents of this type for treatment of high blood pressure.
Parkinson's disease is a chronic, progressive disease that primarily affects older patients. It is characterized by an inability to control the voluntary motor system, and by an inability to initiate voluntary movements. Currently it is treated by giving L-DOPA, a precursor for dopamine in the central nervous system. In the later stages of the disease, it is treated by administering dopamine-like agents such as bromocriptine (Parlodel) marketed by Sandoz pharmaceuticals.
Schizophrenia is a severe mental disorder where patients are unable to function in society without treatment. They have delusions, hallucinations, and thought disorders that affect their perceptions of reality. Currently, schizophrenia is treated with chlorpormazine (Thorazine) or haloperidol (Haldol). These drugs block the acute hallucinations and severe thought disorders of schizophrenia, but leave the intellect of treated patients "blunted". Additional side effects produced by those drugs include a drug-induced Parkinson's syndrome, where voluntary movement is inhibited, and a long-term side effect known as tardive dyskinesia, which includes facial tics and uncontrollable lip and tongue movements. Thorazine has been the most widely used anti-schizophrenic agent and has been in use for more than 25 years. Both Thorazine and Haldol are believed to act by occupying dopamine receptors of the D-2 classification, but they do not elicit a dopamine-like response. Instead, these drugs are dopamine D-2 receptor blocking agents, or antagonists. Recently there has been great interest in developing drugs that will block another type of dopamine receptor, the dopamine D-1 receptor subtype. Great excitement was generated by the discovery that a compound known as SCH 23390, developed by Schering-Plough pharmaceuticals, was a specific dopamine D-1 receptor blocker. However, clinical trials with that drug failed due to toxicity problems. Thus far, no company has been able to develop a dopamine D-1 specific antagonist for evaluation as an antipsychotic agent.
The present invention provides novel compounds, designated generally as substituted trans-5,6,6a,7, 8, 12b-hexahydrobenzo[a]phenanthridines. The biological activities of the present compounds range from potent dopamine-like activity affecting both D-1 and D-2 dopamine receptor subtypes to specific dopamine D-1 receptor antagonist activity. They can be administered by oral or parenteral routes of administration in amounts effective to produce, for example, anti-hypertensive, anti-Parkinson or anti-psychotic responses.
FIG. 1 illustrates the chemical conversions detailed in Example 1 for preparation of a compound of the present invention.
FIG. 2 illustrates chemical conversions detailed in Example 2 for preparation of compounds of the present invention.
There is provided by this invention hexahydrobenzo[a]phenanthridine compounds of the general formula ##STR2## wherein Ha and Hb are trans across ring fusion bond c, R is hydrogen or C1 -C4 alkyl; R1 is hydrogen, benzoyl or pivaloyl; and X is hydrogen, chloro, bromo, iodo or a group of the formula --OR2 wherein R2 is hydrogen, benzoyl or pivaloyl. In another embodiment of this invention when X is a group of the formula --OR2 the groups R1 and R2 can be taken together to form a --CH2 -- group, thus representing a methylenedioxy functional group bridging the C-10 and C-11 (see ring carbon numbering in Formula I) positions on the hexahydrobenzo[a]phenanthridine ring system.
Preferred compounds in accordance with this invention are represented by the formula ##STR3## wherein R, R1 and X are as defined above.
The term C1 -C4 alkyl as used herein refers to methyl, ethyl, propyl, alkyl and cyclopropylmethyl. The selectivity of the present compounds for the dopamine D-1 and D-2 receptors are affected by the nature of the nitrogen substituent. Optimal dopamine D-1 agonist activity has been noted where R in Formula I or Formula II above is hydrogen or methyl.
N-Alkylation may be effected by a variety of methods, including, but not limited to, reductive animation of the compounds wherein R=H with an aldehyde and a reducing agent, treatment with an alkyl halide, treatment with a carboxylic acid in the presence of sodium borohydride, or treatment with carboxylic acid anhydrides followed by reduction, for example with lithium aluminum hydride or with borane.
All active compounds of the present invention bear an oxygen atom at the C-11 position as shown in Formulas I and II above. The C-10 unsubstituted, C-11 hydroxy compounds Possess dopamine D-1 antagonist, or weak agonist activity, depending on the alkyl group that is attached to the nitrogen atom. The most potent dopamine D-1 agonist compounds have a 10,11-dioxy substitution pattern, in particular, the 10,11-dihydroxy substituents. Compound potency and receptor selectivity in this series can be affected by the nature of the nitrogen substituent. The 10,11-dioxy substituents need not be in the form of hydroxyl groups. Masked hydroxyl groups, or prodrug (hydroxyl protecting) groups may also be used. For example, esterification of the 10,11-hydroxyl groups with, for example, benzoic acid or pivalic acid ester forming compounds (e.g., acid anhydrides) yield 10,11-dibenzoyl or dipivaloyl esters that are useful as prodrugs, i.e., they will be hydrolyzed in vivo to produce the biologically active 10,11-dihydroxy compound. A variety of biologically acceptable carboxylic acids may be used to accomplish this. Furthermore, the 10,11-dioxy ring substitution may be in the form of a 10,11-methylenedioxy group. In vivo, body metabolism will cleave this linkage to provide the more active 10,11-dihydroxy functionality.
Dopamine D-1 antagonists in accordance with this invention can bear a C-11 hydroxy with a halogen atom at the C-10 position, where the halogen atom can be bromo, chloro, or iodo. The iodo or bromo groups, for example, may also be a radioactive isotope, so that the resulting radioactive 10-halogen-11-hydroxy substituted compound can be used as a label in receptor binding studies.
While the bromination of the 11-hydroxy compound using elemental bromine has been illustrated in the examples, those skilled in the art may use a variety of halogenating conditions, employing either the 11-hydroxy or the 11-methoxy as substrates. Furthermore, the 11-oxy substituent compounds may also be nitrated in the C-10 position, followed by reduction to the amino compound, which can then also be transformed into a halo substituent via the diazonium salt.
The compounds of this invention can be formulated in conventional dosage forms for parenteral or oral administration. Preferred doses of the present compounds depend on many factors including the indication being treated, the route of administration and the overall condition of the patient. For oral administration effective doses of the present compounds are expected to range from about 0.5 mg/kg to about 50 mg/kg. Effective parenteral doses can range from about 0.1 to about 5 mg/kg.
PAC Example 1. (See FIG. 1)To a solution of 4.50 g (21.8 mmol) of 6,7-dimethoxy-β-tetralone in 100 ml of toluene was added 2.46 g (23 mmol) of benzylamine. The reaction was heated at reflux overnight under N2 with continuous water removal. The reaction was cooled, and the solvent was removed by rotary vacuum evaporation to yield the crude N-benzyl enamine as a brown oil.
This residue was dissolved in 80 ml of CH2 Cl2, and to this was added 2.43 g (24 mmol) of triethylamine, and the solution was cooled in an ice bath. Benzoyl chloride (3.37 g, 24 mmol) was then dissolved in 15 ml of CH2 Cl2 and this solution was then added dropwise to the cold stirring N-benzyl enamine solution. After complete addition the reaction was allowed to warm to room temperature and was left to stir overnight. The mixture was then washed successively with 2×50 ml of 5% aqueous HCl, 2×50 ml of 1 N NaOH, saturated NaCl solution, and was then dried over MgSO4. After filtration, the filtrate was concentrated under vacuum. Crystallization from diethyl ether gave 5.6 g (64%) of the enamide, mp 109°-110°C IR (KBr); 1620 cm/-1 ; CIMS (isobutane); M+1 400; 1 H-NMR (CDCl3); δ 7.64 (m, 2, ArH), 7.33 (m, 8, ArH), 6.52 (s, 1, ArH), 6.38 (s, 1, ArH), 6.05 (s, 1, ArCH), 4.98 (s, 2, ArCH2 N), 3.80 (s, 3, OCH3), 3.78 (s, 3, OCH3), 2.47 (t, 2, CH2, J=8.1 Hz), 2.11 (t, 2, Ch2, J=8.1 Hz); Anal. (C26 H25 NO3) C, H, N.
A solution of 3.14 g (7.85 mmol) of the 6,7-dimethoxy enamide prepared above, in 300 ml of THF, was introduced into an Ace Glass 250 ml photochemical reactor. This solution was stirred while irradiating for 5 hours with a 450 watt Hanovia medium pressure, quartz, mercury-vapor lamp seated in a water cooled, quartz immersion well. The solution was concentrated in vacuo and crystallized from ether to provide 1.345 g (42.9%) of the 10,11-dimethoxy-lactam, mp 183°-186°C IR (KBr); 1655, 1640 cm-1 ; CIMS (isobutane); M+1 400; 1 H-NMR (CDCl3); δ 8.19 (m, 1 ArH), 7.52 (m, 1, ArH), 7.46 (m, 2, ArH), 7.26 (m, 5, ArH), 6.92 (s, 1, ArH), 6.63 (s, 1, ArH), 5.35 (d, 1, ArCH2 N, J=16.0 Hz), 4.78 (d, 1, ArCH2 N, J= 16.0 Hz), 4.37 (d, 1, Ar2 CH, J=11.3 Hz), 3.89 (s, 3, OCH3), 3.88 (s, 3, OCH3), 3.80 (m, 1 CHN), 2.67 (m, 2, ArCH2), 2.25 (m, 1, CH2 CN), 1.75 (m, 1, CH2 CN), Anal. (C26 H25 NO3) C, H, N.
A solution of 1.20 g (3 mmol) of the lactam prepared above, in 100 ml of dry THF was cooled in an ice-salt bath and 6.0 ml of 1 molar solution of BH3 was added via syringe. The reaction was heated at reflux overnight. Water (10 ml) was added dropwise, and the reaction mixture was concentrated by distillation at atmospheric pressure. The residue was stirred with 50 ml of toluene, 1.0 ml of methane sulfonic acid was added, and the mixture was heated with stirring on the steam bath for one hour. The mixture was diluted with 40 ml of water and the aqueous layer was separated. The toluene was extracted several times with water, and the aqueous layers were combined. After basification of the aqueous phase with conc. ammonium hydroxide, the free base was extracted into 5×25 ml of CH2 Cl2. This organic extract was washed with satd NaCl solution, and dried over MgSO4. After filtration, the organic solution was concentrated under vacuum, the residue was taken up into ethanol, and carefully acidified with conc HCl. After drying several times by azeotropic distillation of ethanol, the product was crystallized from ethanol to afford 0.97 g (76.5%) of the salt, mp 235°-237° C. CIMS (NH3); M+1 386; 1 H-NMR (CDCl3, free base); δ 7.37 (m, 9 ArH), 6.89 (s, 1, ArH), 6.74 (s, 1, ArH) 4.07 (d, 1, Ar2 CH, J=10.7 (Hz), 3.90 (s, 3, OCH3) 3.82 (m, 2, ArCH2 N), 3.79 (s, 3, OCH3), 3.52 (d, 1 ArCH2 N, J=15.3 Hz), 3.30 (d, 1, ArCH2), J=13.1 Hz), 2.86 (m, 2, CHN, ArCH2), 2.30 (m, 2, ArCH2, CH2 CN), 1.95 (m, 1, CH2 CN).
A solution of 0.201 g (.48 mmol) of the 6-benzyl hydrochloride salt prepared above in 50 ml of 95% ethanol containing 50 mg of 10% Pd-C catalyst was shaken at room temperature under 50 psig of H2 for 8 hours. After removal of the catalyst by filtration, the solution was concentrated to dryness under vacuum and the residue was recrystallized from acetonitrile to afford 0.119 g (75%) of crystalline salt, mp 243°-244°C CIMS (NH3); M+1 296; 1 H-NMR (CDCl3, free base); δ 7.46 (d, 1, ArH, J=6.1 Hz), 7.24 (m, 3, ArH), 6.91 (s, 1, ArH), 6.74 (s, 1, ArH), 4.09 (s, 2, ArCH2 N), 3.88 (s, 3, OCH3), 3.78 (m, 4, OCH3, Ar2 CH), 2.87 (m, 3, CHN, ArCH2), 2.17 (m, 1, CH2 CN), 1.61 (m, 2, NH, CH2 CN).
A suspension of 0.109 g (0.33 mmol) of the 0,0-dimethyl salt obtained from the reduction above, in 1.5 ml of 48% HBr, was heated at reflux, under N2, for 3 hours. The reaction mixture was concentrated to dryness under high vacuum. This material was dissolved in water and neutralized to the free base with NaHCO3, while cooling the solution in an ice bath. The free base was extracted into chloroform, dried, filtered and concentrated in vacuo. The residue was dissolved in ethanol and carefully neutralized with conc. HCl. After removal of the volatiles, the salt was crystallized as a solvate from methanol. This afforded 30 mg (25.2%) of the desired salt, solvated with a stoichiometry of 1 molecule of amine salt and 1.8 molecules of CH3 OH, as pale yellow crystals, mp 195°C CIMS (isobutane); M+1 268; 1 H-NMR (DMSO, HBr salt); δ 9.40 (bs, 1, + NH2), 9.22 (bs, 1, + NH2 ), 8.76 (bs, 2, OH), 7.38 (m, 4, ArH), 6.72 (s, 1, ArH), 6.63 (s, 1, ArH), 4.40 (s, 2, ArCH2 N+), 4.16 (d, 1, Ar2 CH, J=11.1 Hz), 3.00 (m, 1, CHN+), 2.75 (m, 2, ArCH2), 2.17 (m, 1, CH2 CN+), 1.90 (m, 1, CH2 CN+).
By a similar series of reactions, 7-methoxy-β-tetralone was converted into Trans-11-methoxy-5,6,6a,7, 8,12b-hexahydrobenzo[a]phenanthridine. Some of the reaction methods are described in detail; in cases where the procedures were identical, only the analytical data are provided.
A solution of 20.0 g (0.113 mol) of 7-methoxy-β-tetralone and 12.77 g (0.119 mol) benzylamine in 250 ml of benzene was heated under N2 for 3 hours in an oil bath at 100°C with continuous water removal, at which point 2.0 ml water had been collected. The heat was removed and the mixture was concentrated in vacuo, providing a brown oil.
The crude enamine was dissolved in 500 ml CH2 Cl2, 12.3 g (120 mmol) of triethylamine was added, and the mixture was cooled under N2 and in an ice water bath. This was followed by the addition of 17.15 g (0.12 mol) of benzoyl chloride, in 2 ml aliquots. The solution was allowed to come to room temperature while stirring overnight. The reaction mixture was washed with 2×50 ml of 5% HCl, 2×50 ml of 1 N NaOH, and water, then dried (MgSO4) and filtered through a silica gel plug and Celite. Concentration in vacuo yielded a foam which was then crystallized from ether, which was collected by filtration to provide 24.83 g (59.2%) of enamide, mp 94.5°-95.5°C Another 10.22 g of product was obtained by crystallization of the filtrate for a total yield of 83.6%. IR (KBr); 1620 cm-1 ; CIMS (isobutane); M+1 370; 1 H-NMR (CDCl3); δ 7.62 (m, 2, ArH), 7.33 (m, 8, ArH), 6.88 (d, 1, ArH, J=8.0 Hz) 6.60 (dd, 1, ArH, J=8.0 Hz, J=2.7 Hz), 6.40 (d, 1, ArH, J=2.7 Hz), 6.10 (s, 1, ArCH), 5.00 (s, 2, ArCH2 N), 3.71 (s, 3, OCH3), 2.48 (t, 2, CH2, J=7.9 Hz), 2.11 (t, 2, CH2, J=7.9 Hz); Anal. (C25 H23 NO2) C, H, N.
A solution of 24.321 g (65.8 mmol) of the 7-methoxy-enamide prepared above in 300 ml of THF was introduced into an Ace Glass 250 ml photochemical reactor. This solution was stirred while irradiating for 10 hours with a 450 watt Hanovia medium pressure, quartz, mercury-vapor lamp seated in a water cooled, quartz immersion well. The solution was concentration in vacuo and crystallized from ether to provide 16.97 g (69.8%) of the 11-methoxy-lactam, mp 128°-129°C IR (KBr); 1650, 1630 cm-1 ; CIMS (isobutane); M+1 370; 1 H-NMR (CDCl3); δ 8.19 (m, 1 ArH), 7.55 (m, 1, ArH), 7.46 (m, 2, ArH), 7.27 (m, 5, ArH), 7.08 (d, 1, ArH, J=8.6 Hz), 6.98 (d, 1, ArH, J=2.4 Hz), 6.80 (dd, 1, ArH, J=8.6 Hz, J=2.4 Hz), 5.34 (d, 1, ArCH2 N, J=16.1 Hz), 4.80 (d, 1, ArCH2 N, J=16.1 Hz), 4.40 (d, 1, Ar2 CH, J=11.3 Hz), 3.83 (m, 4, OCH3, CHN), 2.70 (m, 2, ArCH2), 2.27 (m, 1, CH2 CN), 1.74 (m, 1, CH2 CN), Anal. (C26 H25 NO3) C, H, N.
As described in Example 1, the lactam prepared above was reduced with diborane and isolated to afford typical yields of 85-90%. Melting pts.: free base 118°-120°C, HCl Salt 205°-208°C (recrystallized from ethanol). CIMS (NH3): M+1 356. 1 H-NMR (CDCl3, free base); δ 7.34 (m, 10, ArH), 6.88 (d, 1, ArH, J=2.5 Hz), 6.72 (dd, 1, ArH, J=8.3 Hz, J=2.5 Hz), 4.10 (d, 1, Ar2 CH, J=10.7 Hz), 3.96 (d, 1, ArCH2 N, J=13.1 Hz), 3.78 (d, 1, ArCH2 N, J=15.2 Hz), 3.72 (s, 3, OCH3), 3.47 (d, 1, ArCH2 N, J=15.2 Hz), 3.28 (d, 1, ArCH2 N, J=13.1 Hz), 2.91 (m, 2, ArCH2, CHN), 2.40 (m, 1, ArCH2 ), 2.20 (m, 1, CH2 CN), 2.00 (m, 1, CH2 CN). Anal. (C25 H26 ClNO) C, H, Cl, N.
As described in Example 1, the 6-benzyl amine hydrochloride prepared above was reduced catalytically at 50 psig H2 in ethanol over 10% Pd-C catalyst, to afford typical yields of 75-95%. Melting point: HCl Salt 233°C, (recrystallized from ethanol). CIMS (NH3): M+1 266; 1 H-NMR (CDCl3, HCl Salt); δ 7.45 (d, 1, ArH, J=4.3 Hz), 7.34 (m, 3, ArH), 7.14 (d, 1, ArH, J=7.8 Hz), 6.92 (d, 1, ArH, J=2.7 Hz); 6.80 (dd, 1, ArH, J=7.8 Hz, J=2.7 Hz), 4.45 (m, 3, ArCH2 N+, Ar2 CH), 3.80 (s, 3, OCH3), 3.10 (m, 1, CHN+), 2.90 (m, 2, ArCH2), 2.51 (m, 1, CH2 CN+) 2.39 (m, 1, CH2 CN+), Anal. (C18 H20 ClNO) C, H, Cl, N.
(See FIG. 2) To a solution of 1.081 g (3.42 mmol of 11-methoxy-hexahydrobenzo[a]phenanthridine hydrochloride in 30 ml of methanol was added 1.85 ml (66.8 mmol) of 37% formalin solution, followed by 0.93 g (14.8 mmol) of NaCNBH3. After stirring at room temperature overnight, the volatiles were removed in vacuo, the residue was diluted with 50 ml of 2N HCl, stirred for 45 min. and washed with 3×15 ml of diethyl ether. The aqueous fraction was made basic with NaOH pellets and then extracted with 3×30 ml CH2 Cl2. The combined dichloromethane fractions were dried (MgSO4), filtered and concentrated in vacuo to give 1.02 g (100%) of the free base as a colorless oil. The oil was dissolved in abs. ethanol, acidified with conc. HCl, dried by azeotropic distillation of ethanol, and was then crystallized from absolute ethanol. This provided 0.947 g (84%) of the amine hydrochloride, mp 215°-218°C CIMS (NH3): M+1 280; 1 H-NMR (CDCl3, free base); δ 7.40 (d, 1, ArH, J=7 Hz), 7.24 (m, 2, ArH), 7.13 (m, 2, ArH), 6.81 (d, 1, ArH, J=2.7 Hz); 6.72 (dd, 1, ArH, J=8 Hz, J=2.7 Hz), 4.02 (d, 1, Ar2 CH, J=9.9 Hz), 3.84 (d, 1, ArCH2 N, J=15.0 Hz), 3.72 (s, 3, OCH3), 3.50 (d, 1, ArCH2 N, J=15.0 Hz), 2.89 (m, 2, ArCH2, CHN) 2.39 (s, 3, NCH3), 2.08 (m, 2, ArCH2, CH2 CN), 1.92 (m, 1, CH2 CN).
(See FIG. 2) A suspension of 0.456 g. (1.44 mmol) of 11-methoxy-6- methyl-hexahydrobenzo[a]phenanthridine hydrochloride in 10 ml 48% HBr was heated for 2.5 hours at reflux under N2 in an oil bath. The heat was removed, and the reaction mixture was placed in the refrigerator overnight. The white precipitate was collected by suction filtration, and after washing the crystals on the filter with cold ethanol and ether, the product weighed 403 mg (80.6%), mp 251°-254°C The filtrate was concentrated and the residue was crystallized from ethanol to provide additional product, giving essentially a quantitative total yield of the phenol, mp 254°C CIMS (NH3): M+1 266; 1 H-NMR (CDCl3, free base); δ 7.38 (d, 1, ArH, J=7.5 Hz), 7.22 (m, 3, ArH), 7.04 (d, 1, ArH, J=8.2 Hz), 6.69 (s, 1, ArH); 6.64 (d, 1, ArH, J=8.2 Hz,) 3.98 (d, 1, Ar2 CH), 3.84 (d, 1, ArCH2 N, J=14.5 Hz), 3.50 (d, 1, ArCH2 N, J=14.5 Hz), 2.87 (m, 2, CH2 and CHN) 2.38 (s, 3, NCH3), 2.09 (m, 2, CH), 1.86 (m, 1, CH2 CN).
(See FIG. 2) A solution of 0.300 g (0.866 mol) of 11-hydroxy-6-methyl-hexahydrobenzo[a]phenanthridine hydrobromide in 100 ml water was made basic with conc. NH4 OH. The precipitate was removed by suction filtration, washed with water and dried to provide 0.23 g (100%) of the free base. This was dissolved in 100 ml of glacial acetic acid under N2, and the solution was cooled to 10°C with a water bath. To this was added 53 ml of a 16.455 millimolar solution of Br2 in glacial acetic acid (0.872 mmol Br2), with stirring. The solution was allowed to warm to room temperature and was stirred overnight. The brominated compound precipitated and was removed by suction filtration and was washed on the filter with ether. The pale off-white solid weighed 0.165 g (44.8%), mp 270°C Recrystalliation from methanol provided an analytical sample, mp 275°-277°C CIMS (NH3): M+1 344, 346; 1 H-NMR (CDCl3, free base); 7.19 (m, 5, ArH), 6.88 (s, 1, ArH), 3.94 (d, 1, Ar2 CH, J=9.5 Hz), 3.86 (d, 1, ArCH2 N, J.=16.3 Hz), 3.50 (s, 1, ArCH2 N, J=16.3 Hz), 2.80 (m, 2, ArCH, CHN) 2.38 (s, 3, NCH3), 2.07 (m, 3, ArCH, CH2 CN). Anal. (C18 H19 BrClNO): C, H, N.
| Patent | Priority | Assignee | Title |
| 10111960, | Jan 12 2004 | THE TRUSTREES OF THE UNIVERSITY OF PENNSYLVANIA | 9-OH-risperidone controlled release composition |
| 10736965, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Risperidone biodegradable implant |
| 5420134, | May 26 1992 | Purdue Research Foundation; University of North Carolina at Chapel Hill | Substituted hexahydrobenzo[A]phenanthridines |
| 5597832, | Apr 06 1993 | AbbVie Inc | Tetracyclic compounds as dopamine agonists |
| 5659037, | Aug 18 1994 | Abbott Laboratories | Process for preparing chiral tetracyclic dopaminergic compounds |
| 5668141, | Apr 02 1996 | AbbVie Inc | Trans-2,6-,3,6-and 4,6-diaza-5,6,6a,7,8,12b-hexahydrobenzo[c]phenanthrene compounds as dopamine agonists |
| 5744476, | Jun 27 1994 | Interneuron Pharmaceuticals, Inc. | Dopamine D1 agonists for the treatment of dementia |
| 5959110, | Aug 18 1995 | Purdue Research Foundation; University of North Carolina | Fused isoquinolines as dopamine receptor ligands |
| 6194423, | Aug 18 1995 | Purdue Research Foundation; University of North Carolina at Chapel Hill | Fused isoquinolines as dopamine receptor ligands |
| 7091212, | Aug 10 2001 | Purdue Research Foundation | Chiral dinapsoline |
| 7220754, | Feb 15 2002 | DarPharma, Inc. | Mono-ester and asymmetrically substatuted di-ester pro-drugs of dopamide D1 receptor agonists |
| 7666445, | Oct 20 2000 | The Trustees of the University of Pennsylvania | Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use |
| 8318938, | Feb 21 2006 | Purdue Research Foundation | Trans-fused chromenoisoquinolines synthesis and methods for use |
| 8741327, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Method of maintaining therapeutic risperidone levels in a PLA:PLGA implant |
| 8758795, | Oct 20 2000 | The Trustees of the University of Pennsylvania | Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use |
| 8802127, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Risperidone-containing PLA:PGA implants and methods of use thereof |
| 9359303, | Apr 21 2009 | Purdue Research Foundation | Octahydrobenzoisoquinoline modulators of dopamine receptors and uses therefor |
| 9439905, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Risperidone-containing implants and methods of use thereof |
| 9717799, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Drug-containing implants and methods of use thereof |
| 9895447, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Drug-containing PLA implants and methods of use thereof |
| 9925268, | Jan 12 2004 | The Trustees of the University of Pennsylvania | Drug-containing implants and methods of use thereof |
| Patent | Priority | Assignee | Title |
| 3912740, | |||
| 3939165, | Nov 14 1974 | NORWICH EATON PHARMACEUTICALS, INC , A CORP OF OH | 5,6,6A,6B,7,8-Hexahydrobenz[a]phenanthridine hydrochloride |
| 4737503, | Oct 08 1986 | VIPONT LABORATORIES, INC | Method for inhibiting the release of histamine |
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